Fluorinated 3-(2-oxo-3-(3-arylpropyl)imidazolidin-1-y1)-3-arylpropanoic acid derivatives

ABSTRACT

The invention relates to fluorinated compounds and their use as integrin receptor antagonists. Novel fluorinated 3-(2-oxo-3-(3-arylpropyl)imidazolidin-1-yl)-3-arylpropanoic acid derivatives and pharmaceutically acceptable salts or solvates thereof and their use are described.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.14/175,501, filed on Feb. 7, 2014, allowed, which claims priority to andthe benefit of U.S. Provisional Application No. 61/762,087, filed onFeb. 7, 2013, the contents of each of which are incorporated herein byreference in their entireties.

BACKGROUND

It is believed that a wide variety of disease states and conditions canbe mediated by acting on integrin receptors and that integrin receptorantagonists represent a useful class of drugs. Integrin receptors areheterodimeric transmembrane proteins through which cells attach andcommunicate with extracellular matrices and other cells. Antagonists ofthe integrin receptors αvβ3, αvβ5, and/or αvβ6are useful for inhibitingbone resorption, treating and preventing osteoporosis, and inhibitingvascular restenosis, diabetic retinopathy, macular degeneration,angiogenesis, atherosclerosis, inflammation, wound healing, viraldisease, tumor growth, and metastasis.

SUMMARY OF THE INVENTION

The invention relates to novel fluorinated3-(2-oxo-3-(3-arylpropyl)imidazolidin-1-yl)-3-arylpropanoic acidderivatives and their use as integrin receptor antagonists. Thesecompounds or pharmaceutically acceptable salts or solvates thereof areuseful for example in inhibiting bone resorption, treating or preventingosteoporosis, or inhibiting vascular restenosis, diabetic retinopathy,macular degeneration, angiogenesis, atherosclerosis, inflammation, woundhealing, viral disease, tumor growth, or metastasis.

The invention provides a compound of formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein X, Y,R₁, R₂ and R₃ are as described herein and provided that the compound offormula I contains at least one fluorine atom.

The invention relates to pharmaceutical compositions comprising one ofthe compounds of the invention as an active ingredient. In one aspect,the invention provides a pharmaceutical composition comprising at leastone compound of formula I, II, III, IV, or V or a pharmaceuticallyacceptable salt or solvate thereof and one or more pharmaceuticallyacceptable carriers, diluents, or excipients.

The invention relates to pharmaceutical compositions. The inventionprovides a pharmaceutical composition comprising a compound of theinvention or a pharmaceutically acceptable salt or solvate thereof andone or more pharmaceutically acceptable carriers, diluents, orexcipients, and which further comprises an active ingredient selectedfrom the group consisting of a) an organic bisphosphonate or apharmaceutically acceptable salt or ester thereof, b) an estrogenreceptor modulator, c) a cytotoxic/antiproliferative agent, d) a matrixmetalloproteinase inhibitor, e) an inhibitor of epidermal-derived,fibroblast-derived, or platelet-derived growth factors, f) an inhibitorof VEGF, g) an inhibitor of Flk-1/KDR, Flt-1, Tck/Tie-2, or Tic-1, h) acathepsin K inhibitor, and i) a prenylation inhibitor, such as afarnesyl transferase inhibitor or a geranylgeranyl transferase inhibitoror a dual farnesyl/geranylgeranyl transferase inhibitor; and mixturesthereof.

The invention provides a pharmaceutical composition comprising acompound of the invention or a pharmaceutically acceptable salt orsolvate thereof and one or more pharmaceutically acceptable carriers,diluents, or excipients, and which further comprises an activeingredient selected from the group consisting of a) an organicbisphosphonate or a pharmaceutically acceptable salt or ester thereof b)an estrogen receptor modulator, and c)a cathepsin K inhibitor; andmixtures thereof. In one aspect, the organic bisphosphonate orpharmaceutically acceptable salt or ester thereof is alendronatemonosodium trihydrate.

The invention provides a pharmaceutical composition comprising acompound of the invention or a pharmaceutically acceptable salt orsolvate thereof and one or more pharmaceutically acceptable carriers,diluents, or excipients, and which further comprises an activeingredient selected from the group consisting of a) acytotoxic/antiproliferative agent, b)a matrix metalloproteinaseinhibitor, c) an inhibitor of epidermal-derived, fibroblast-derived, orplatelet-derived growth factors, d) an inhibitor of VEGF, and e) aninhibitor of Flk-1/KDR, Flt-1, Tck/Tie-2, or Tie-1; and mixturesthereof.

The invention relates to a method of eliciting an integrin receptorantagonizing effect in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound of the invention or a pharmaceutically acceptable salt orsolvate, thereof. In one aspect, the integrin receptor antagonizingeffect is an αvβ3 antagonizing effect. In one aspect, the αvβ3antagonizing effect is selected from the group consisting of inhibitionof bone resorption, restenosis, angiogenesis, diabetic retinopathy,macular degeneration, inflammation, viral disease, tumor growth, andmetastasis. In one aspect, the αvβ3 antagonizing effect is theinhibition of bone resorption.

In one aspect, the integrin receptor antagonizing effect is an αvβ5antagonizing effect. In one aspect, the αvβ5 antagonizing effect isselected from the group consisting of inhibition of restenosis,angiogenesis, diabetic retinopathy, macular degeneration, inflammation,tumor growth, and metastasis.

In one aspect, the integrin receptor antagonizing effect is a dualαvβ3/αvβ5 antagonizing effect. In one aspect, the dual αvβ3/αvβ5antagonizing effect is selected from the group consisting of inhibitionof bone resorption, restenosis, angiogenesis, diabetic retinopathy,macular degeneration, inflammation, viral disease, tumor growth, andmetastasis.

In one aspect, the integrin antagonizing effect is an αvβ6 antagonizingeffect. In one aspect, the αvβ6 antagonizing effect is selected from thegroup consisting of angiogenesis, inflammatory response, and woundhealing.

The invention relates to a method of eliciting an integrin receptorantagonizing effect in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of apharmaceutical composition comprising a compound of the invention or apharmaceutically acceptable salt or solvate thereof and one or morepharmaceutically acceptable carriers, diluents, or excipients.

The invention relates to methods for the use of compounds of theinvention. The compounds of the invention have a useful pharmacologicalactivity spectrum and are therefore particularly suitable for theprevention and/or treatment of a condition.

The invention provides a method of treating and/or preventing acondition in a subject comprising administering to the subject in needthereof an effective amount of a compound of the invention or apharmaceutically acceptable salt or solvate thereof. In one aspect, theinvention provides treating a condition. In one aspect, the inventionprovides preventing a condition.

The invention provides a method of treating and/or preventing acondition in a subject comprising administering to the subject in needthereof an effective amount of a compound of the invention or apharmaceutically acceptable salt or solvate, thereof, wherein thecondition is mediated by antagonism of an integrin receptor. In oneaspect, the invention provides treating a condition mediated byantagonism of an integrin receptor. In one aspect, the inventionprovides preventing a condition mediated by antagonism of an integrinreceptor.

The invention provides a method of inhibiting bone resorption in asubject in need thereof, comprising administering to the subject atherapeutically effective amount of a pharmaceutical compositioncomprising a compound of the invention or a pharmaceutically acceptablesalt or solvate thereof and one or more pharmaceutically acceptablecarriers, diluents, or excipients.

The invention provides a method of inhibiting bone resorption in asubject in need thereof, comprising administering to the subject atherapeutically effective amount of a pharmaceutical compositioncomprising a compound of the invention or a pharmaceutically acceptablesalt or solvate thereof and one or more pharmaceutically acceptablecarriers, diluents, or excipients, and which further comprises an activeingredient selected from the group consisting of a) an organicbisphosphonate or a pharmaceutically acceptable salt or ester thereof,b) an estrogen receptor modulator, and c) a cathepsin K inhibitor; andmixtures thereof.

The invention provides a method of treating tumor growth in a subject inneed thereof, comprising administering to the subject a therapeuticallyeffective amount of a pharmaceutical composition comprising a compoundof the invention or a pharmaceutically acceptable salt or solvatethereof and one or more pharmaceutically acceptable carriers, diluents,or excipients, and which further comprises an active ingredient selectedfrom the group consisting of a) a cytotoxic/antiproliferative agent, b)a matrix metalloproteinase inhibitor, c) an inhibitor ofepidermal-derived, fibroblast-derived, or platelet-derived growthfactors, d) an inhibitor of VEGF, and e) an inhibitor of Flk-1/KDR,Flt-1, Tck/Tie-2, or Tie-1; and mixtures thereof.

The invention provides a method of treating a condition in a subjectcomprising administering to the subject in need thereof an effectiveamount of a compound of the invention or a pharmaceutically acceptablesalt or solvate, thereof, in combination with radiation therapy whereinthe condition is tumor growth.

DETAILED DESCRIPTION OF THE INVENTION

For purposes of the invention, the following definitions will be used(unless expressly stated otherwise):

“A compound of the invention” or “compounds of the invention” refers toa compound(s) disclosed herein e.g., a compound(s) of the inventionincludes a compound(s) of any of the formulae described herein includingformula I, II, III, IV, or V and/or a compound(s) explicitly disclosedherein. Whenever the term is used in the context of the invention it isto be understood that the reference is being made to the free base andthe corresponding pharmaceutically acceptable salts or solvates thereof,provided that such is possible and/or appropriate under thecircumstances.

“Pharmaceutical” or “pharmaceutically acceptable” when used herein as anadjective, means substantially non-toxic and substantiallynon-deleterious to the recipient.

By “pharmaceutical composition” it is further meant that the carrier,solvent, excipient(s) and salt must be compatible with the activeingredient of the formulation (e.g. a compound of the invention). It isunderstood by those of ordinary skill in this art that the terms“pharmaceutical formulation” and “pharmaceutical composition” aregenerally interchangeable, and they are so used for the purposes of thisapplication.

Some of the compounds of the invention may exist in unsolvated as wellas solvated forms such as, for example, hydrates.

“Solvate” means a solvent addition form that contains either astoichiometric or non-stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate. In the hydrates, the water moleculesare attached through secondary valencies by intermolecular forces, inparticular hydrogen bridges. Solid hydrates contain water as so-calledcrystal water in stoichiometric ratios, where the water molecules do nothave to be equivalent with respect to their binding state. Examples ofhydrates are sesquihydrates, monohydrates, dihydrates or trihydrates.Equally suitable are the hydrates of salts of the compounds of theinvention

The invention also includes one or more metabolites of a compound of theinvention.

For use in medicine, the salts of the compounds of the invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of the compounds according to theinvention or of their pharmaceutically acceptable salts. Saltsencompassed within the term “pharmaceutically acceptable salts” refer tonon-toxic salts of the compounds of the invention which are generallyprepared by reacting the free base with a suitable organic or inorganicacid. Representative salts include the following: acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, calcium, camsylate, carbonate, chloride, clavulanate, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate,pamottle(embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate,tannate, tartrate, teoclate, tosylate, triethiodide and valerate.Furthermore, where the compounds of the invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof may includealkali metal salts, e.g., sodium or potassium salts; alkaline earthmetal salts, e.g., calcium or magnesium salts; and salts formed withsuitable organic ligands, e.g., quaternary ammonium salts which may bederived from ammonia or organic amines, such as, for example,diethylamine, triethylamine, ethyldiisopropylamine, procaine,dibenzylamine, N-methylmorpholine, dihydroabietylamine ormethylpiperidine.

The invention includes within its scope prodrugs of the compounds of theinvention. In general, such prodrugs will be functional derivatives ofthe compounds of the invention which are readily convertible in vivointo the required compound. Thus, in the methods of treatment of theinvention, the term “administering” shall encompass the treatment of thevarious conditions described with the compound specifically disclosed orwith a compound which may not be specifically disclosed, but whichconverts to the specified compound in vivo after administration to thepatient. Conventional procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in “Design ofProdrugs,” ed. H. Bundgaard, Elsevier, 1985. Metabolites of thesecompounds include active species produced upon introduction of compoundsof the invention into the biological milieu.

“Therapeutically effective amount” refers to that amount of a drug orpharmaceutical agent that will elicit the biological or medical responseof a tissue, system, animal or human that is being sought by aresearcher or clinician.

The compounds of the invention may contain one or more asymmetriccenters and can thus occur as racemates and racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers.Additional asymmetric centers may be present depending upon the natureof the various substituents on the molecule. Each such asymmetric centerwill independently produce two optical isomers and it is intended thatall of the possible optical isomers and diastereomers in mixtures and aspure or partially purified compounds are included within the ambit ofthe invention. The invention is meant to comprehend all such isomericforms of these compounds.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as contacting a racemicmixture of compounds with an enantiomerically pure compound to form adiastereomeric mixture, followed by separation of the individualdiastereomers by standard methods, such as fractional crystallization orchromatography. The diasteriomeric mixture is often a mixture ofdiasteriomeric salts which is formed by contacting a racemic mixture ofcompounds with an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

“Treat,” “treating,” or “treatment” refers to decreasing the symptoms,markers, and/or any negative effects of a condition in any appreciabledegree in a subject who currently has the condition. In someembodiments, treatment may be administered to a subject who exhibitsonly early signs of the condition for the purpose of decreasing the riskof developing the disease, disorder, and/or condition.

“Prevent,” “prevention,” or “preventing” refers to any method topartially or completely prevent or delay the onset of one or moresymptoms or features of a disease, disorder, and/or condition.Prevention may be administered to a subject who does not exhibit signsof a disease, disorder, and/or condition.

“Subject” means a human or animal (in the case of an animal, moretypically a mammal). In one aspect, the subject is a human.

“Fluorinated derivative” is a derivative compound that has the samechemical structure as the original compound, except that at least oneatom is replaced with a fluorine atom or with a group of atomscontaining at least one fluorine atom.

“Integrin receptor antagonist” refers to a compound which binds to andantagonizes either the αvβ3 receptor, the αvβ5 receptor, or the αvβ6receptor, or a compound which binds to and antagonizes combinations ofthese receptors (for example, a dual αvβ3/αvβ5 receptor antagonist).

“Bone resorption” refers to the process by which osteoclasts degradebone.

“Alkoxy” refers to straight or branched chain alkoxides of the number ofcarbon atoms specified (e.g., C₁-C₆ alkoxy), or any number within thisrange (i.e., methoxy, ethoxy, etc.).

The problem to be solved by the invention is the identification of novelcompounds which are antagonists of the integrin receptors αvβ3, αvβ5,and/or αvβ6 and are useful for inhibiting bone resorption, treating orpreventing osteoporosis, or inhibiting vascular restenosis, diabeticretinopathy, macular degeneration, angiogenesis, atherosclerosis,inflammation, wound healing, viral disease, tumor growth, or metastasis.Although integrin-targeted drugs are available, these drugs are oftennot suitable for patients for a variety of reasons. For example, theavailable antibody based therapies are often associated with a high costof production, have an inconvenient mode of administration, and have apropensity for host immunogenicity and infusion reactions, and theavailable peptide-based drugs may lack specificity and requireinjections or intravenous administration, have high production costs,and limited stability. Small molecules represent another class ofintegrin-targeted drugs, however the compounds currently in the clinicand underdevelopment tend to be zwitterionic in nature and generallyencounter limitations in bioavailability, serum protein binding, andintegrin selectivity. Many integrin receptor antagonists are associatedwith undesired adverse effects. The invention provides the solution ofnew fluorinated integrin receptor antagonists useful for example ininhibiting bone resorption, treating or preventing osteoporosis, orinhibiting vascular restenosis, diabetic retinopathy, maculardegeneration, angiogenesis, atherosclerosis, inflammation, woundhealing, viral disease, tumor growth, or metastasis. The fluorinatedcompounds of the invention have advantages such as providing improvedpotency, selectivity, tissue penetration, half-life, and/or metabolicstability.

Compounds of the Invention

The present invention relates to novel fluorinated3-(2-oxo-3-(3-arylpropyl)imidazolidin-1-yl)-3-arylpropanoic acidderivatives and their use.

In one aspect, the invention provides a compound of formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein

-   X is selected from CH and N;-   Y is selected from CH and N;-   R₁ is C₁-C₆ alkoxy wherein said C₁-C₆ alkoxy is substituted with 0,    1, 2, 3, 4, or 5 fluorine atoms; and-   R₂ and R₃ are each independently selected from H and F,-   or R₂ and R₃ taken together with the carbon atom to which they are    attached form a 3- or 4-membered carbocyclic or heterocyclic ring,    provided that the compound of formula I contains at least one    fluorine atom.

In one aspect, the invention provides a compound of formula II:

or a pharmaceutically acceptable salt or solvate thereof, wherein

-   X is selected from CH and N;-   Y is selected from CH and N;-   R₁ is C₁-C₆ alkoxy wherein said C₁-C₆ alkoxy is substituted with 0,    1, 2, 3, 4, or 5 fluorine atoms; and-   R₂ and R₃ are each independently selected from H and F,-   or R₂ and R₃ taken together with the carbon atom to which they are    attached form a 3- or 4-membered carbocyclic or heterocyclic ring,    provided that the compound of formula II contains at least one    fluorine atom.

In one aspect, the invention provides a compound of formula I or II,wherein X is CH. In one aspect, the invention provides a compound offormula I or II, wherein X is N. In one aspect, the invention provides acompound of formula I or II, wherein Y is CH. In one aspect, theinvention provides a compound of formula I or II, wherein Y is N. In oneaspect, the invention provides a compound of formula I or II, wherein Xor Y is CH and the remaining X or Y is N. In one aspect, the inventionprovides a compound of formula I or II, wherein X is N and Y is CH. Inone aspect, the invention provides a compound of formula I or II,wherein X is CH and Y is N. In one aspect, the invention provides acompound of formula I or II, wherein X and Y are both CH. In one aspect,the invention provides a compound of formula I or II, wherein X and Yare both N.

In one aspect, the invention provides a compound of formula I or II,wherein R₁ is C₁-C₆ alkoxy substituted with 1, 2, 3, 4, or 5 fluorineatoms. In one aspect, the invention provides a compound of formula I orII, wherein R₁ is C₁-C₆ alkoxy substituted with 2 or 3 fluorine atoms.In one aspect, the invention provides a compound of formula I or II,wherein R₁ is selected from OCH₃, OCH₂F, OCHF₂, OCF₃, and OCH₂CH₃. Inone aspect, the invention provides a compound of formula I or II,wherein R₁ is selected from OCH₂F, OCHF₂, and OCF₃. In one aspect, theinvention provides a compound of formula I or II, wherein R₁ is selectedfrom OCH₃ and OCH₂CH₃. In one aspect, the invention provides a compoundof formula I or II, wherein R₁ is selected from OCH₃ and OCHF₂. In oneaspect, the invention provides a compound of formula I or II, wherein R₁is OCH₃. In one aspect, the invention provides a compound of formula Ior II, wherein R₁ is OCHF₂.

In one aspect, the invention provides a compound of formula I or II,wherein R₂ is H. In one aspect, the invention provides a compound offormula I or II, wherein R₂ is F. In one aspect, the invention providesa compound of formula I or II, wherein R₃ is H. In one aspect, theinvention provides a compound of formula I or II, wherein R₃ is F. Inone aspect, the invention provides a compound of formula I or II,wherein one of R₂ or R₃ is H, and the remaining R₂ or R₃ is F. In oneaspect, the invention provides a compound of formula I or II, wherein R₂is H and R₃ is F. In one aspect, the invention provides a compound offormula I or II, wherein R₂ is F and R₃ is H. In one aspect, theinvention provides a compound of formula I or II, wherein R₂ and R₃ areboth H. In one aspect, the invention provides a compound of formula I orII, wherein R₂ and R₃ are both F. In one aspect, the invention providesa compound of formula I or II, wherein R₂ and R₃ taken together with thecarbon atom to which they are attached form a 4-membered heterocyclicring. In one aspect, the invention provides a compound of formula I orII, wherein the 4-membered heterocyclic ring is an oxetane ring. In oneaspect, the invention provides a compound of formula I or II, whereinthe oxetane ring is an oxetan-3-yl ring. In one aspect, the inventionprovides a compound of formula I or II, wherein the oxetane ring is anoxetan-2-yl ring.

In one aspect, the invention provides a compound of formula III:

or a pharmaceutically acceptable salt or solvate thereof, wherein

-   R₁ is C₁-C₆ alkoxy wherein said C₁-C₆ alkoxy is substituted with 0,    1, 2, 3, 4, or 5 fluorine atoms; and-   R₂ and R₃ are each independently selected from H and F,-   or R₂ and R₃ taken together with the carbon atom to which they are    attached form a 3- or 4-membered carbocyclic or heterocyclic ring,    provided that the compound of formula III contains at least one    fluorine atom.

In one aspect, the invention provides a compound of formula III, whereinR₁ is C₁-C₆ alkoxy substituted with 1, 2, 3, 4, or 5 fluorine atoms. Inone aspect, the invention provides a compound of formula III, wherein R₁is C₁-C₆ alkoxy substituted with 2 or 3 fluorine atoms. In one aspect,the invention provides a compound of formula III, wherein R₁ is selectedfrom OCH₃, OCH₂F, OCHF₂, OCF₃, and OCH₂CH₃. In one aspect, the inventionprovides a compound of formula III, wherein R₁ is selected from OCH₂F,OCHF₂, and OCF₃. In one aspect, the invention provides a compound offormula III, wherein R₁ is selected from OCH₃ and OCH₂CH₃. In oneaspect, the invention provides a compound of formula III, wherein R₁ isselected from OCH₃ and OCHF₂. In one aspect, the invention provides acompound of formula III, wherein R₁ is OCH₃. In one aspect, theinvention provides a compound of formula III, wherein R₁ is OCHF₂.

In one aspect, the invention provides a compound of formula III, whereinR₂ is H. In one aspect, the invention provides a compound of formulaIII, wherein R₂ is F. In one aspect, the invention provides a compoundof formula III, wherein R₃ is H. In one aspect, the invention provides acompound of formula III, wherein R₃ is F. In one aspect, the inventionprovides a compound of formula III, wherein one of R₂ or R₃ is H, andthe remaining R₂ or R₃ is F. In one aspect, the invention provides acompound of formula III, wherein R₂ is H and R₃ is F. In one aspect, theinvention provides a compound of formula III, wherein R₂ is F and R₃ isH. In one aspect, the invention provides a compound of formula III,wherein R₂ and R₃ are both H. In one aspect, the invention provides acompound of formula III, wherein R₂ and R₃ are both F. In one aspect,the invention provides a compound of formula III, wherein R₂ and R₃taken together with the carbon atom to which they are attached form a4-membered heterocyclic ring. In one aspect, the invention provides acompound of formula III, wherein the 4-membered heterocyclic ring is anoxetane ring. In one aspect, the invention provides a compound offormula III, wherein the oxetane ring is an oxetan-3-yl ring. In oneaspect, the invention provides a compound of formula III, wherein theoxetane ring is an oxetan-2-yl ring.

In one aspect, the invention provides a compound of formula IV:

or a pharmaceutically acceptable salt or solvate thereof, wherein

-   R₁ is C₁-C₆ alkoxy wherein said C₁-C₆ alkoxy is substituted with 0,    1, 2, 3, 4, or 5 fluorine atoms; and-   R₂ and R₃ are each independently selected from H and F,-   or R₂ and R₃ taken together with the carbon atom to which they are    attached form a 3- or 4-membered carbocyclic or heterocyclic ring,    provided that the compound of formula IV contains at least one    fluorine atom.

In one aspect, the invention provides a compound of formula IV, whereinR₁ is C₁-C₆ alkoxy substituted with 1, 2, 3, 4, or 5 fluorine atoms. Inone aspect, the invention provides a compound of formula IV, wherein R₁is C₁-C₆ alkoxy substituted with 2 or 3 fluorine atoms. In one aspect,the invention provides a compound of formula IV, wherein R₁ is selectedfrom OCH₃, OCH₂F, OCHF₂, OCF₃, and OCH₂CH₃. In one aspect, the inventionprovides a compound of formula IV, wherein R₁ is selected from OCH₂F,OCHF₂, and OCF₃. In one aspect, the invention provides a compound offormula IV, wherein R₁ is selected from OCH₃ and OCH₂CH₃. In one aspect,the invention provides a compound of formula IV, wherein R₁ is selectedfrom OCH₃ and OCHF₂. In one aspect, the invention provides a compound offormula IV, wherein R₁ is OCH₃. In one aspect, the invention provides acompound of formula IV, wherein R₁ is OCHF₂.

In one aspect, the invention provides a compound of formula IV, whereinR₂ is H. In one aspect, the invention provides a compound of formula IV,wherein R₂ is F. In one aspect, the invention provides a compound offormula IV, wherein R₃ is H. In one aspect, the invention provides acompound of formula IV, wherein R₃ is F. In one aspect, the inventionprovides a compound of formula IV, wherein one of R₂ or R₃ is H, and theremaining R₂ or R₃ is F. In one aspect, the invention provides acompound of formula IV, wherein R₂ is H and R₃ is F. In one aspect, theinvention provides a compound of formula IV, wherein R₂ is F and R₃ isH. In one aspect, the invention provides a compound of formula IV,wherein R₂ and R₃ are both H. In one aspect, the invention provides acompound of formula IV, wherein R₂ and R₃ are both F. In one aspect, theinvention provides a compound of formula IV, wherein R₂ and R₃ takentogether with the carbon atom to which they are attached form a4-membered heterocyclic ring. In one aspect, the invention provides acompound of formula IV, wherein the 4-membered heterocyclic ring is anoxetane ring. In one aspect, the invention provides a compound offormula IV, wherein the oxetane ring is an oxetan-3-yl ring. In oneaspect, the invention provides a compound of formula IV, wherein theoxetane ring is an oxetan-2-yl ring.

In one aspect, the invention provides a compound of formula V:

or a pharmaceutically acceptable salt or solvate thereof, wherein

-   R₁ is C₁-C₆ alkoxy wherein said C₁-C₆ alkoxy is substituted with 0,    1, 2, 3, 4, or 5 fluorine atoms; and-   R₂ and R₃ are each independently selected from H and F,-   or R₂ and R₃ taken together with the carbon atom to which they are    attached form a 3- or 4-membered carbocyclic or heterocyclic ring,    provided that the compound of formula V contains at least one    fluorine atom.

In one aspect, the invention provides a compound of formula V, whereinR₁ is C₁-C₆ alkoxy substituted with 1, 2, 3, 4, or 5 fluorine atoms. Inone aspect, the invention provides a compound of formula V, wherein R₁is C₁-C₆ alkoxy substituted with 2 or 3 fluorine atoms. In one aspect,the invention provides a compound of formula V, wherein R₁is selectedfrom OCH₃, OCH₂F, OCHF₂, OCF₃, and OCH₂CH₃. In one aspect, the inventionprovides a compound of formula V, wherein R₁is selected from OCH₂F,OCHF₂, and OCF₃. In one aspect, the invention provides a compound offormula V, wherein R₁is selected from OCH₃ and OCH₂CH₃. In one aspect,the invention provides a compound of formula V, wherein R₁ is selectedfrom OCH₃ and OCHF₂. In one aspect, the invention provides a compound offormula V, wherein R₁ is OCH₃. In one aspect, the invention provides acompound of formula V, wherein R₁ is OCHF₂. In one aspect, the inventionprovides a compound of formula V, wherein R₂ is H. In one aspect, theinvention provides a compound of formula V, wherein R₂ is F. In oneaspect, the invention provides a compound of formula V, wherein R₃ is H.In one aspect, the invention provides a compound of formula V, whereinR₃ is F. In one aspect, the invention provides a compound of formula V,wherein one of R₂ or R₃ is H, and the remaining R₂ or R₃ is F. In oneaspect, the invention provides a compound of formula V, wherein R₂ is Hand R₃ is F. In one aspect, the invention provides a compound of formulaV, wherein R₂ is F and R₃ is H. In one aspect, the invention provides acompound of formula V, wherein R₂ and R₃ are both H. In one aspect, theinvention provides a compound of formula V, wherein R₂ and R₃ are bothF. In one aspect, the invention provides a compound of formula V,wherein R₂ and R₃ taken together with the carbon atom to which they areattached form a 4-membered heterocyclic ring. In one aspect, theinvention provides a compound of formula V, wherein the 4-memberedheterocyclic ring is an oxetane ring. In one aspect, the inventionprovides a compound of formula V, wherein the oxetane ring is anoxetan-3-yl ring. In one aspect, the invention provides a compound offormula V, wherein the oxetane ring is an oxetan-2-yl ring.

A compound of formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein

-   X is selected from CH and N;-   Y is selected from CH and N;-   R₁ is C₁-C₆ alkoxy wherein said C₁-C₆ alkoxy is substituted with 0,    1, 2, 3, 4, or 5 fluorine atoms; and-   R₂ and R₃ are each independently selected from H and F,-   or R₂ and R₃ taken together with the carbon atom to which they are    attached form a 3- or 4-membered carbocyclic or heterocyclic ring,    provided that the compound of formula I contains at least one    fluorine atom.

A compound of formula II:

or a pharmaceutically acceptable salt or solvate thereof, wherein

-   X is selected from CH and N;-   Y is selected from CH and N;-   R₁ is C₁-C₆ alkoxy wherein said C₁-C₆ alkoxy is substituted with 0,    1, 2, 3, 4, or 5 fluorine atoms; and-   R₂ and R₃ are each independently selected from H and F,-   or R₂ and R₃ taken together with the carbon atom to which they are    attached form a 3- or 4-membered carbocyclic or heterocyclic ring,    provided that the compound of formula II contains at least one    fluorine atom.

A compound of paragraph [001] or [002], comprising a compound of formulaI or II, wherein X is CH.

A compound of paragraph [001] or [002], comprising a compound of formulaI or II, wherein X is N.

A compound of paragraph [001] or [002], comprising a compound of formulaI or II, wherein Y is CH.

A compound of paragraph [001] or [002], comprising a compound of formulaI or II, wherein Y is N.

A compound of paragraph [001] or [002], comprising a compound of formulaI or II, wherein X or Y is CH and the remaining X or Y is N.

A compound of paragraph [001] or [002], comprising a compound of formulaI or II, wherein X is N and Y is CH.

A compound of paragraph [001] or [002], comprising a compound of formulaI or II, wherein X is CH and Y is N.

A compound of paragraph [001] or [002], comprising a compound of formulaI or II, wherein X and Y are both CH.

A compound of paragraph [001] or [002], comprising a compound of formulaI or II, wherein X and Y are both N

A compound as in one of paragraphs [001] through [011], comprising acompound of formula I or II, wherein said C₁-C₆ alkoxy is substitutedwith 1, 2, 3, 4, or 5 fluorine atoms.

A compound of paragraph [012], comprising a compound of formula I or II,wherein said C₁-C₆ alkoxy is substituted with 2 or 3 fluorine atoms.

A compound as in one of paragraphs [001] through [011], comprising acompound of formula I or II, wherein R₁is selected from OCH₃, OCH₂F,OCHF₂, OCF₃, and OCH₂CH₃.

A compound of paragraph [013] or [014], comprising a compound of formulaI or II, wherein R₁is selected from OCH₂F, OCHF₂, and OCF₃.

A compound of paragraph [014], comprising a compound of formula I or II,wherein R₁is selected from OCH₃ and OCH₂CH₃.

A compound of paragraph [014], comprising a compound of formula I or II,wherein R₁ is selected from OCH₃ and OCHF₂.

A compound of paragraph [017], comprising a compound of formula I or II,wherein R₁ is OCH₃.

A compound of paragraph [017], comprising a compound of formula I or II,wherein R₁ is OCHF₂.

A compound as in one of paragraphs [001] through [019], comprising acompound of formula I or II, wherein R₂ is H.

A compound as in one of paragraphs [001] through [019], comprising acompound of formula I or II, wherein R₂ is F.

A compound as in one of paragraphs [001] through [019], comprising acompound of formula I or II, wherein R₃ is H.

A compound as in one of paragraphs [001] through [019], comprising acompound of formula I or II, wherein R₃ is F.

A compound as in one of paragraphs [001] through [019], comprising acompound of formula I or II, wherein one of R₂ or R₃ is H, and theremaining R₂ or R₃ is F.

A compound as in one of paragraphs [001] through [019], comprising acompound of formula I or II, wherein R₂ is H and R₃ is F.

A compound as in one of paragraphs [001] through [019], comprising acompound of formula I or II, wherein R₂ is F and R₃ is H.

A compound as in one of paragraphs [001] through [019], comprising acompound of formula I or II, wherein R₂ and R₃ are both H.

A compound as in one of paragraphs [001] through [019], comprising acompound of formula I or II, wherein R₂ and R₃ are both F.

A compound as in one of paragraphs [001] through [019], comprising acompound of formula I or II, wherein R₂ and R₃ taken together with thecarbon atom to which they are attached form a 4-membered heterocyclicring.

A compound of paragraph [029], comprising a compound of formula I or II,wherein the 4-membered heterocyclic ring is an oxetane ring.

A compound of paragraph [030], comprising a compound of formula I or II,wherein the oxetane ring is an oxetan-3-yl ring.

A compound of paragraph [030], comprising a compound of formula I or II,wherein the oxetane ring is an oxetan-2-yl ring.

A compound of formula III:

or a pharmaceutically acceptable salt or solvate thereof, wherein

-   R₁ is C₁-C₆ alkoxy wherein said C₁-C₆ alkoxy is substituted with 0,    1, 2, 3, 4, or 5 fluorine atoms; and-   R₂ and R₃ are each independently selected from H and F,-   or R₂ and R₃ taken together with the carbon atom to which they are    attached form a 3- or 4-membered carbocyclic or heterocyclic ring,    provided that the compound of formula III contains at least one    fluorine atom.

A compound of paragraph [033], comprising a compound of formula III,wherein said C₁-C₆ alkoxy is substituted with 1, 2, 3, 4, or 5 fluorineatoms.

A compound of paragraph [034], comprising a compound of formula III,wherein said C₁-C₆ alkoxy is substituted with 2 or 3 fluorine atoms.

A compound of paragraph [033], comprising a compound of formula III,wherein R₁is selected from OCH₃, OCH₂F, OCHF₂, OCF₃, and OCH₂CH₃.

A compound of paragraph [035] or [036], comprising a compound of formulaIII, wherein R₁is selected from OCH₂F, OCHF₂, and OCF₃.

A compound of paragraph [036], comprising a compound of formula III,wherein R₁is selected from OCH₃ and OCH₂CH₃.

A compound of paragraph [036], comprising a compound of formula III,wherein R₁ is selected from OCH₃ and OCHF₂.

A compound of paragraph [039], comprising a compound of formula III,wherein R₁ is OCH₃.

A compound of paragraph [039], comprising a compound of formula III,wherein R₁ is OCHF₂.

A compound as in one of paragraphs [033] through [041], comprising acompound of formula III, wherein R₂ is H.

A compound as in one of paragraphs [033] through [041], comprising acompound of formula III, wherein R₂ is F.

A compound as in one of paragraphs [033] through [041], comprising acompound of formula III, wherein R₃ is H.

A compound as in one of paragraphs [033] through [041], comprising acompound of formula III, wherein R₃ is F.

A compound as in one of paragraphs [033] through [041], comprising acompound of formula III, wherein one of R₂ or R₃ is H, and the remainingR₂ or R₃ is F.

A compound as in one of paragraphs [033] through [041], comprising acompound of formula III, wherein R₂ is H and R₃ is F.

A compound as in one of paragraphs [033] through [041], comprising acompound of formula III, wherein R₂ is F and R₃ is H.

A compound as in one of paragraphs [033] through [041], comprising acompound of formula III, wherein R₂ and R₃ are both H.

A compound as in one of paragraphs [033] through [041], comprising acompound of formula III, wherein R₂ and R₃ are both F.

A compound as in one of paragraphs [033] through [041], comprising acompound of formula III, wherein R₂ and R₃ taken together with thecarbon atom to which they are attached form a 4-membered heterocyclicring.

A compound of paragraph [051], comprising a compound of formula III,wherein the 4-membered heterocyclic ring is an oxetane ring.

A compound of paragraph [052], comprising a compound of formula III,wherein the oxetane ring is an oxetan-3-yl ring.

A compound of paragraph [052], comprising a compound of formula III,wherein the oxetane ring is an oxetan-2-yl ring.

A compound of formula IV:

or a pharmaceutically acceptable salt or solvate thereof, wherein

-   R₁ is C₁-C₆ alkoxy wherein said C₁-C₆ alkoxy is substituted with 0,    1, 2, 3, 4, or 5 fluorine atoms; and-   R₂ and R₃ are each independently selected from H and F,-   or R₂ and R₃ taken together with the carbon atom to which they are    attached form a 3- or 4-membered carbocyclic or heterocyclic ring,    provided that the compound of formula IV contains at least one    fluorine atom.

A compound of paragraph [055], comprising a compound of formula IV,wherein said C₁-C₆ alkoxy is substituted with 1, 2, 3, 4, or 5 fluorineatoms.

A compound of paragraph [056], comprising a compound of formula IV,wherein said C₁-C₆ alkoxy is substituted with 2 or 3 fluorine atoms.

A compound of paragraph [055], comprising a compound of formula IV,wherein R₁is selected from OCH₃, OCH₂F, OCHF₂, OCF₃, and OCH₂CH₃.

A compound of paragraph [057] or [058], comprising a compound of formulaIV, wherein R₁is selected from OCH₂F, OCHF₂, and OCF₃.

A compound of paragraph [058], comprising a compound of formula IV,wherein R₁is selected from OCH₃ and OCH₂CH₃.

A compound of paragraph [058], comprising a compound of formula IV,wherein R₁ is selected from OCH₃ and OCHF₂.

A compound of paragraph [061], comprising a compound of formula IV,wherein R₁ is OCH₃.

A compound of paragraph [061], comprising a compound of formula IV,wherein R₁ is OCHF₂.

A compound as in one of paragraphs [055] through [063], comprising acompound of formula IV, wherein R₂ is H.

A compound as in one of paragraphs [055] through [063], comprising acompound of formula IV, wherein R₂ is F.

A compound as in one of paragraphs [055] through [063], comprising acompound of formula IV, wherein R₃ is H.

A compound as in one of paragraphs [055] through [063], comprising acompound of formula IV, wherein R₃ is F.

A compound as in one of paragraphs [055] through [063], comprising acompound of formula IV, wherein one of R₂ or R₃ is H, and the remainingR₂ or R₃ is F.

A compound as in one of paragraphs [055] through [063], comprising acompound of formula IV, wherein R₂ is H and R₃ is F.

A compound as in one of paragraphs [055] through [063], comprising acompound of formula IV, wherein R₂ is F and R₃ is H.

A compound as in one of paragraphs [055] through [063], comprising acompound of formula IV, wherein R₂ and R₃ are both H.

A compound as in one of paragraphs [055] through [063], comprising acompound of formula IV, wherein R₂ and R₃ are both F.

A compound as in one of paragraphs [055] through [063], comprising acompound of formula IV, wherein R₂ and R₃ taken together with the carbonatom to which they are attached form a 4-membered heterocyclic ring.

A compound of paragraph [073], comprising a compound of formula IV,wherein the 4-membered heterocyclic ring is an oxetane ring.

A compound of paragraph [074], comprising a compound of formula IV,wherein the oxetane ring is an oxetan-3-yl ring.

A compound of paragraph [074], comprising a compound of formula IV,wherein the oxetane ring is an oxetan-2-yl ring.

A compound of formula V:

or a pharmaceutically acceptable salt or solvate thereof, wherein

-   R₁ is C₁-C₆ alkoxy wherein said C₁-C₆ alkoxy is substituted with 0,    1, 2, 3, 4, or 5 fluorine atoms; and-   R₂ and R₃ are each independently selected from H and F,-   or R₂ and R₃ taken together with the carbon atom to which they are    attached form a 3- or 4-membered carbocyclic or heterocyclic ring,    provided that the compound of formula V contains at least one    fluorine atom.

A compound of paragraph [077], comprising a compound of formula V,wherein said C₁-C₆ alkoxy is substituted with 1, 2, 3, 4, or 5 fluorineatoms.

A compound of paragraph [078], comprising a compound of formula V,wherein said C₁-C₆ alkoxy is substituted with 2 or 3 fluorine atoms.

A compound of paragraph [077], comprising a compound of formula V,wherein R₁is selected from OCH₃, OCH₂F, OCHF₂, OCF₃, and OCH₂CH₃.

A compound of paragraph [079] or [080], comprising a compound of formulaV, wherein R₁is selected from OCH₂F, OCHF₂, and OCF₃.

A compound of paragraph [080], comprising a compound of formula V,wherein R₁is selected from OCH₃ and OCH₂CH₃.

A compound of paragraph [080], comprising a compound of formula V,wherein R₁ is selected from OCH₃ and OCHF₂.

A compound of paragraph [083], comprising a compound of formula V,wherein R₁ is OCH₃.

A compound of paragraph [083], comprising a compound of formula V,wherein R₁ is OCHF₂.

A compound as in one of paragraphs [077] through [085], comprising acompound of formula V, wherein R₂ is H.

A compound as in one of paragraphs [077] through [085], comprising acompound of formula V, wherein R₂ is F.

A compound as in one of paragraphs [077] through [085], comprising acompound of formula V, wherein R₃ is H.

A compound as in one of paragraphs [077] through [085], comprising acompound of formula V, wherein R₃ is F.

A compound as in one of paragraphs [077] through [085], comprising acompound of formula V, wherein one of R₂ or R₃ is H, and the remainingR₂ or R₃ is F.

A compound as in one of paragraphs [077] through [085], comprising acompound of formula V, wherein R₂ is H and R₃ is F.

A compound as in one of paragraphs [077] through [085], comprising acompound of formula V, wherein R₂ is F and R₃ is H.

A compound as in one of paragraphs [077] through [085], comprising acompound of formula V, wherein R₂ and R₃ are both H.

A compound as in one of paragraphs [077] through [085], comprising acompound of formula V, wherein R₂ and R₃ are both F.

A compound as in one of paragraphs [077] through [085], comprising acompound of formula V, wherein R₂ and R₃ taken together with the carbonatom to which they are attached form a 4-membered heterocyclic ring.

A compound of paragraph [095], comprising a compound of formula V,wherein the 4-membered heterocyclic ring is an oxetane ring.

A compound of paragraph [096], comprising a compound of formula V,wherein the oxetane ring is an oxetan-3-yl ring.

A compound of paragraph [096], comprising a compound of formula V,wherein the oxetane ring is an oxetan-2-yl ring.

A compound selected from:

Com- pound # Chemical Structure A1

A2

A3

A4

A5

A6

A7

A8

or a pharmaceutically acceptable salt or solvate thereof.

A pharmaceutical composition comprising a compound or a pharmaceuticallyacceptable salt or solvate thereof as in one of paragraphs [001] through[099] and a pharmaceutical carrier, diluent, or excipient.

The composition of paragraph [100] which further comprises an activeingredient selected from the group consisting of

-   a) an organic bisphosphonate or a pharmaceutically acceptable salt    or ester thereof,-   b) an estrogen receptor modulator,-   c) a cytotoxic/antiproliferative agent,-   d) a matrix metalloproteinase inhibitor,-   e) an inhibitor of epidermal-derived, fibroblast-derived, or    platelet-derived growth factors,-   f) an inhibitor of VEGF,-   g) an inhibitor of Flk-1/KDR, Flt-1, Tck/Tie-2, or Tic-1,-   h) a cathepsin K inhibitor, and-   i) a prenylation inhibitor, such as a farnesyl transferase inhibitor    or a geranylgeranyl transferase inhibitor or a dual    farnesyl/geranylgeranyl transferase inhibitor; and mixtures thereof.

The composition of paragraph [101] wherein said active ingredient isselected from the group consisting of

-   a) an organic bisphosphonate or a pharmaceutically acceptable salt    or ester thereof,-   b) an estrogen receptor modulator, and-   c) a cathepsin K inhibitor; and mixtures thereof.

The composition of paragraph [102] wherein said organic bisphosphonateor pharmaceutically acceptable salt or ester thereof is alendronatemonosodium trihydrate.

The composition of paragraph [101] wherein said active ingredient isselected from the group consisting of

-   a) a cytotoxic/antiproliferative agent,-   b) a matrix metalloproteinase inhibitor,-   c) an inhibitor of epidermal-derived, fibroblast-derived, or    platelet-derived growth factors,-   d) an inhibitor of VEGF, and-   e) an inhibitor of Flk-1/KDR, Flt-1, Tck/Tie-2, or Tie-1; and    mixtures thereof.

A method of eliciting an integrin receptor antagonizing effect in asubject in need thereof, comprising administering to the subject atherapeutically effective amount of a compound or a pharmaceuticallyacceptable salt or solvate as in one of paragraphs [001] through [099].

The method of paragraph [105] wherein the integrin receptor antagonizingeffect is an αvβ3 antagonizing effect.

The method of paragraph [106] wherein the αvβ3 antagonizing effect isselected from the group consisting of inhibition of bone resorption,restenosis, angiogenesis, diabetic retinopathy, macular degeneration,inflammation, viral disease, tumor growth, and metastasis.

The method of paragraph [107] wherein the αvβ3 antagonizing effect isthe inhibition of bone resorption.

The method of paragraph [105] wherein the integrin receptor antagonizingeffect is an αvβ5 antagonizing effect.

The method of paragraph [109] wherein the αvβ5 antagonizing effect isselected from the group consisting of inhibition of restenosis,angiogenesis, diabetic retinopathy, macular degeneration, inflammation,tumor growth, and metastasis.

The method of paragraph [105] wherein the integrin receptor antagonizingeffect is a dual αvβ3/αvβ5 antagonizing effect.

The method of paragraph [111] wherein the dual αvβ3/αvβ5 antagonizingeffect is selected from the group consisting of inhibition of boneresorption, restenosis, angiogenesis, diabetic retinopathy, maculardegeneration, inflammation, viral disease, tumor growth, and metastasis.

The method of paragraph [105] wherein the integrin antagonizing effectis an αvβ6 antagonizing effect.

The method of paragraph [113] wherein the αvβ6 antagonizing effect isselected from the group consisting of angiogenesis, inflammatoryresponse, and wound healing.

A method of eliciting an integrin receptor antagonizing effect in asubject in need thereof, comprising administering to the subject atherapeutically effective amount of the composition of paragraph [100].

A method of treating and/or preventing a condition in a subjectcomprising administering to the subject in need thereof an effectiveamount of a compound or a pharmaceutically acceptable salt or solvatethereof as in one of paragraphs [001] through [099].

The method of paragraph [116], wherein the condition is mediated byantagonism of an integrin receptor.

A method of inhibiting bone resorption in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of the composition of paragraph [100].

A method of inhibiting bone resorption in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of the composition of paragraph [102].

A method of treating tumor growth in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of the composition of paragraph [104].

A method of treating tumor growth in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound as in one of paragraphs [001] through [099] incombination with radiation therapy.

A method of synthesizing a compound or a pharmaceutically acceptablesalt or solvate thereof as in one of paragraphs [001] through [099].

In one aspect, the invention provides a compound or a pharmaceuticallyacceptable salt or solvate thereof of Table 1.

TABLE 1 Com- pound # Chemical Structure A1

A2

A3

A4

A5

A6

A7

A8

In one aspect, a compound of the invention is a pharmaceuticallyacceptable salt. In one aspect, a compound of the invention is asolvate. In one aspect, a compound of the invention is a hydrate.

The invention relates to pharmaceutical compositions comprising one ofthe compounds of the invention as an active ingredient. In one aspect,the invention provides a pharmaceutical composition comprising at leastone compound of formula I, II, III, IV, or V or a pharmaceuticallyacceptable salt or solvate thereof and one or more pharmaceuticallyacceptable carriers, diluents, or excipients. In one aspect, theinvention provides a pharmaceutical composition comprising at least onecompound of Table 1.

In one aspect, the invention relates to a method of synthesizing acompound of the invention or a pharmaceutically acceptable salt orsolvate thereof.

The invention also comprehends deuterium labeled compounds of formula I,II, III, IV, and V and the compounds listed in Table 1. The deuteriumlabeled compounds comprise a deuterium atom having an abundance ofdeuterium that is substantially greater than the natural abundance ofdeuterium, which is 0.015%.

The term “deuterium enrichment factor” as used herein means the ratiobetween the deuterium abundance and the natural abundance of adeuterium. In one aspect, a compound of the invention has a deuteriumenrichment factor for each deuterium atom of at least 3500 (52.5%deuterium incorporation at each deuterium atom), at least 4000 (60%deuterium incorporation), at least 4500 (67.5% deuterium incorporation),at least 5000 (75% deuterium), at least 5500 (82.5% deuteriumincorporation), at least 6000 (90% deuterium incorporation), at least6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuteriumincorporation), at least 6600 (99% deuterium incorporation), or at least6633.3 (99.5% deuterium incorporation).

Deuterium labeled compounds can be prepared using any of a variety ofart-recognized techniques. For example, deuterium labeled compounds offormula I, II, III, IV, and V and the compounds listed in Table 1 of theinvention can generally be prepared by carrying out the proceduresdisclosed in the Schemes and/or in the Examples described herein, bysubstituting a readily available deuterium labeled reagent for anon-deuterium labeled reagent.

A compound of the invention or a pharmaceutically acceptable salt orsolvate thereof that contains the aforementioned deuterium atom(s) iswithin the scope of the invention. Further, substitution with heavierdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements.

Methods of Use

Representative compounds of the invention typically displaysubmicromolar affinity for the integrin receptors, particularly theαvβ3, αvβ5 and/or αvβ6 receptors. Compounds of the invention aretherefore useful for treating a subject suffering from a bone conditioncaused or mediated by increased bone resorption, who are in need of suchtherapy. Pharmacologically effective amounts of the compounds, includingpharmaceutically acceptable salts thereof, are administered to thesubject, to inhibit the activity of mammalian osteoclasts.

The compounds of the invention are administered in dosages effective toantagonize the αvβ3 receptor where such treatment is needed, as, forexample, in the prevention or treatment of osteoporosis.

Further exemplifying the invention is the method wherein the integrinreceptor antagonizing effect is an αvβ3 antagonizing effect. Anillustration of the invention is the method wherein the αvβ3antagonizing effect is selected from inhibition of bone resorption,restenosis, angiogenesis, diabetic retinopathy, macular degeneration,inflammation, viral disease, tumor growth, or metastasis. In one aspect,the αvβ3 antagonizing effect is the inhibition of bone resorption.

An example of the invention is the method wherein the integrin receptionantagonizing effect is an αvβ5 antagonizing effect. More specifically,the αvβ5 antagonizing effect is selected from inhibition of restenosis,angiogenesis, diabetic retinopathy, macular degeneration, inflammation,tumor growth, or metastasis.

Illustrating the invention is the method wherein the integrin receptorantagonizing effect is a dual αvβ3/αvβ5 antagonizing effect. Moreparticularly, the dual αvβ3/αvβ5 antagonizing is selected frominhibition of bone resorption, restenosis, angiogenesis, diabeticretinopathy, macular degeneration, inflammation, viral disease, tumorgrowth, or metastasis.

Illustrating the invention is the method wherein the integrin receptorantagonizing effect is an αvβ6 antagonizing effect. More particularly,the αvβ6 antagonizing effect is selected from inhibition ofangiogenesis, inflammatory response, or wound healing.

Illustrating the invention is the method wherein the αvβ3 antagonizingeffect is selected from inhibition of bone resorption, inhibition ofrestenosis, inhibition of angiogenesis, inhibition of diabeticretinopathy, inhibition of macular degeneration, inhibition ofatherosclerosis, inflammation, viral disease, or inhibition of tumorgrowth or metastasis. In one aspect, the αvβ3 antagonizing effect is theinhibition of bone resorption.

More particularly illustrating the invention is a pharmaceuticalcomposition comprising any of the compounds described above and apharmaceutically acceptable carrier. Another example of the invention isa pharmaceutical composition made by combining any of the compoundsdescribed above and a pharmaceutically acceptable carrier. Anotherillustration of the invention is a process for making a pharmaceuticalcomposition comprising combining any of the compounds described aboveand a pharmaceutically acceptable carrier.

Illustrating the invention is a method of treating and/or preventing acondition in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of any of the compoundsdescribed above. Further illustrating the invention is a method oftreating and/or preventing a condition mediated by antagonism of anintegrin receptor in a subject in need thereof, comprising administeringto the subject a therapeutically effective amount of any of thecompounds described above. In one aspect, the condition is selected frombone resorption, osteoporosis, restenosis, diabetic retinopathy, maculardegeneration, angiogenesis, atherosclerosis, inflammation, viraldisease, cancer, tumor growth, and metastasis. In one aspect, thecondition is selected from osteoporosis and cancer. In one aspect, thecondition is osteoporosis.

More specifically exemplifying the invention is a method of eliciting anintegrin antagonizing effect in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of anyof the compounds or any of the pharmaceutical compositions describedabove. In one aspect, the integrin antagonizing effect is an αvβ3antagonizing effect; more specifically, the αvβ3 antagonizing effect isselected from inhibition of bone resorption, inhibition of restenosis,inhibition of atherosclerosis, inhibition of angiogenesis, inhibition ofdiabetic retinopathy, inhibition of macular degeneration, inhibition ofinflammation, inhibition of viral disease, or inhibition of tumor growthor metastasis. In one aspect, the αvβ3 antagonizing effect is inhibitionof bone resorption. Alternatively, the integrin antagonizing effect isan αvβ5 antagonizing effect, an αvβ6 antagonizing effect, or a mixedαvβ3, αvβ5, and αvβ6 antagonizing effect. Examples of αvβ5 antagonizingeffects are inhibition of restenosis, atherosclerosis, angiogenesis,diabetic retinopathy, macular degeneration, inflammation, viral disease,or tumor growth. Examples of dual αvβ6 antagonizing effects areinhibition of angiogenesis, inflammatory response and wound healing.

Additional examples of the invention are methods of inhibiting boneresorption and of treating and/or preventing osteoporosis in a subjectin need thereof, comprising administering to the subject atherapeutically effective amount of any of the compounds or any of thepharmaceutical compositions described above.

Additional illustrations of the invention are methods of treatinghypercalcemia of malignancy, osteopenia due to bone metastases,periodontal disease, hyperparathyroidism, periarticular erosions inrheumatoid arthritis, Paget's disease, immobilization-inducedosteopenia, and glucocorticoid treatment in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of any of the compounds or any of the pharmaceutical compositionsdescribed above.

More particularly exemplifying the invention is the use of any of thecompounds described above in the preparation of a medicament for thetreatment and/or prevention of osteoporosis in a subject in needthereof. Still further exemplifying the invention is the use of any ofthe compounds described above in the preparation of a medicament for thetreatment and/or prevention of bone resorption, tumor growth, cancer,restenosis, atherosclerosis, diabetic retinopathy, macular degeneration,inflammation, viral disease, and/or angiogenesis.

Also exemplifying the invention are compositions further comprising anactive ingredient selected from the group consisting of

-   -   a.) an organic bisphosphonate or a pharmaceutically acceptable        salt or ester thereof,    -   b.) an estrogen receptor modulator,    -   c.) a cytototoxic/antiproliferative agent,    -   d.) a matrix metalloproteinase inhibitor,    -   e.) an inhibitor of epidermal-derived, fibroblast-derived, or        platelet-derived growth factors,    -   f.) an inhibitor of VEGF,    -   g.) an inhibitor of Flk-1/KDR, Flt-1, Tck/Tie-2, or Tie-1,    -   h.) a cathespin K inhibitor; and    -   i.) a prenylation inhibitor, such as a farnesyl transferase        inhibitor or a geranylgeranyl transferase inhibitor or a dual        farnesyl/geranylgeranyl transferase inhibitor, and mixtures        thereof.        (See, B. Millauer et al., “Dominant-Negative Inhibition of Flk-1        Suppresses the Growth of Many Tumor Types in Vivo”, Cancer        Research 56, 161514 1620 (1996), which is incorporated by        reference herein in its entirety).

In one aspect, the active ingredient is selected from the groupconsisting of:

a.) an organic bisphosphonate or a pharmaceutically acceptable salt orester thereof,

b.) an estrogen receptor modulator, and

c.) a cathepsin K inhibitor, and mixtures thereof

Nonlimiting examples of such bisphosphonates include alendronate,etidronate, pamidronate, risedronate, ibandronate, and pharmaceuticallyacceptable salts and esters thereof. In one aspect the bisphosphonate isalendronate, e.g. alendronate monosodium trihydrate.

Nonlimiting examples of estrogen receptor modulators include estrogen,progesterin, estradiol, droloxifene, raloxifene, and tamoxifene.

Nonlimiting examples of cytotoxic/antiproliferative agents are taxol,vincristine, vinblastine, and doxorubicin.

Cathepsin K, formerly known as cathepsin O2, is a cysteine protease andis described in PCT International Application Publication No. WO96/13523, published May 9, 1996; U.S. Pat. No. 5,501,969, issued Mar. 3,1996; and U.S. Pat. No. 5,736,357, issued Apr. 7, 1998, all of which areincorporated by reference herein in their entirety. Cysteine proteases,specifically cathepsins, are linked to a number of disease conditions,such as tumor metastasis, inflammation, arthritis, and bone remodeling,At acidic pH's, cathepsins can degrade type-I collagen. Cathepsinprotease inhibitors can inhibit osteoclastic bone resorption byinhibiting the degradation of collagen fibers and are thus useful in thetreatment of bone resorption diseases, such as osteoporosis.

The invention is also directed to combinations of the compounds of theinvention with one or more agents useful in the prevention or treatmentof osteoporosis. For example, the compounds of the instant invention maybe effectively administered in combination with effective amounts ofother agents such as an organic bisphosphonate, an estrogen receptormodulator, or a cathepsin K inhibitor.

Additional illustrations of the invention are methods of inhibiting boneresorption in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of a compound described aboveand one or more agents described above. Additional illustrations of theinvention are methods of treating tumor growth in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a compound described above and one or more agentsknown to be cytotoxic/antiproliferative. Also, the compounds of theinvention can be administered in combination with radiation therapy fortreating tumor growth and metastasis.

In addition, the integrin αvβ3 antagonist compounds of the invention maybe effectively administered in combination with a growth hormonesecretagogue in the therapeutic or prophylactic treatment of disordersin calcium or phosphate metabolism and associated diseases. Thesediseases include conditions which can benefit from a reduction in boneresorption. A reduction in bone resorption should improve the balancebetween resorption and formation, reduce bone loss or result in boneaugmentation. A reduction in bone resorption can alleviate the painassociated with osteolytic lesions and reduce the incidence and/orgrowth of those lesions. These diseases include: osteoporosis (includingestrogen deficiency, immobilization, glucocorticoid induced and senile),osteodystrophy, Paget's disease, myositis ossificans, Bechterew'sdisease, malignant hypercalcemia, metastatic bone disease, periodontaldisease, cholelithiasis, nephrolithiasis, urolithiasis, urinarycalculus, hardening of the arteries (sclerosis), arthritis, bursitis,neuritis and tetany. Increased bone resorption can be accompanied bypathologically high calcium and phosphate concentrations in the plasma,which would be alleviated by this treatment. Similarly, the inventionwould be useful in increasing bone mass in patients with growth hormonedeficiency. Thus, in one aspect, combinations are simultaneous oralternating treatments of an αvβ3 receptor antagonist of the inventionand a growth hormone secretagogue, optionally including a thirdcomponent comprising an organic bisphosphonate, e.g. alendronatemonosodium trihydrate.

In accordance with the method of the invention, the individualcomponents of the combination can be administered separately atdifferent times during the course of therapy or concurrently in dividedor single combination forms. The instant invention is therefore to beunderstood as embracing all such regimens of simultaneous or alternatingtreatment, and the term “administering” is to be interpretedaccordingly. It will be understood that the scope of combinations of thecompounds of the invention with other agents useful for treatingintegrin-mediated conditions includes in principle any combination withany pharmaceutical composition useful for treating osteoporosis.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The compounds of the invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups and emulsions. Likewise, they may also beadministered in intravenous (bolus or in-fusion), intraperitoneal,topical (e.g., ocular eyedrop), subcutaneous, intramuscular ortransdermal (e.g., patch) form, all using forms well known to those ofordinary skill in the pharmaceutical arts. An effective but non-toxicamount of the compound desired can be employed as an αvβ3 antagonist.

The dosage regimen utilizing the compounds of the invention is selectedin accordance with a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the routes of administration; the renal andhepatic function of the patient; and the particular compound or saltthereof employed. An ordinary skilled physician, veterinarian orclinician can readily determine and prescribe the effective amount ofthe drug required to prevent, counter or arrest the progress of thecondition.

Oral dosages of the invention, when used for the indicated effects, willrange between about 0.01 mg per kg of body weight per day (mg/kg/day) toabout 100 mg/kg/day, 0.01 to 10 mg/kg/day, and 0.1 to 5.0 mg/kg/day. Fororal administration, the compositions are provided in the form oftablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0,25.0, 50.0, 100 and 500 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Amedicament typically contains from about 0.01 mg to about 500 mg of theactive ingredient, from about 1 mg to about 100 mg of active ingredient.Intravenously, doses will range from about 0.1 to about 10 mg/kg/minuteduring a constant rate infusion. Advantageously, compounds of theinvention may be administered in a single daily dose, or the total dailydosage may be administered in divided doses of two, three or four timesdaily. Furthermore, compounds of the invention can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal routes, using those forms of transdermal skin patches wellknown to those of ordinary skill in the art. To be administered in theform of a transdermal delivery system, the dosage administration will,of course, be continuous rather than intermittent throughout the dosageregimen.

In the methods of the invention, the compounds herein described indetail can form the active ingredient, and are typically administered inadmixture with suitable pharmaceutical diluents, excipients or carriers(collectively referred to herein as ‘carrier’ materials) suitablyselected with respect to the intended form of administration, that is,oral tablets, capsules, elixirs, syrups and the like, and consistentwith conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes and the like. Lubricants used in these dosageforms include sodium oleate, sodium stearate, magnesium stearate, sodiumbenzoate, sodium acetate, sodium chloride and the like. Disintegratorsinclude, without limitation, starch, methyl cellulose, agar, bentonite,xanthan gum and the like.

The compounds of the invention can also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles. Liposomes can be formedfrom a variety of phospholipids, such as cholesterol, stearylamine orphosphatidylcholines.

Compounds of the invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the invention may also becoupled with soluble polymers as targetable drug carriers. Such polymerscan include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamide-phenol or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of theinvention may be coupled to a class of biodegradable polymers useful inachieving controlled release of a drug, for example, polylactic acid,polyglycolic acid, copolymers of polylactic and polyglycolic acid,polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked oramphipathic block copolymers of hydrogels.

EXAMPLES Experimental Procedures and Compound Characterization Example 1Synthesis of (S)-3-(6-(difluoromethoxy)41yridine-3-yl)-3-(2-oxo-3-(3-(5, 6, 7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl) imidazolidin-1-yl)propanoic acid (Compound A1 in Table 1)

Experimental Details tert-butyl 2-oxopyrrolidine-1-carboxylate (2a)

To a stirred solution of compound 1a (10.0 g, 117 mmol, 1.0 equiv.) inDCM, (Boc)₂O (25.5 g, 117 mmol, 1.00 equiv.) and DMAP (0.022 g, 0.180mmol, 0.001 equiv.) were added at RT and stirred for 12 h. Afterconsumption of the starting material (monitored by TLC), volatiles wereremoved under reduced pressure to afford compound 2a (19.6 g, 90.3%) asa brown syrup.

TLC: 50% EtOAc/Hexane (R_(f): 0.40)

¹H NMR (400 MHz, CDCl₃): δ 3.74 (t, J=6.8 Hz, 2H), 2.50 (t, J=8.0 Hz,2H), 2.01 (t, J=7.6 Hz, 2H), 1.52 (s, 9H)

tert-butyl (5-(dimethoxyphosphoryl)-4-oxopentyl) carbamate (3a)

To a stirred solution of iPr₂NH (2.99 mL, 21.8 mmol, 1.35 equiv.) inTHF, cooled to −10° C., Hexyl Lithium (8.79 mL, 20.0 mmol, 1.24 equiv.)was slowly added. The reaction mixture was cooled to −60° C.,Dimethylmethyl phosphonate (2.20 mL, 20.9 mmol, 1.29 equiv.) was addedand stirred for 1 h, the temperature was raised to −40° C., compound 2a(3.0 g, 16.2 mmol, 1.0 equiv.) was introduced to the reaction mixtureand stirring was continued for further 1 h. After consumption of thestarting material, 2NH₂SO₄ solution (20 mL) was added slowly to thereaction and stirred at 0° C. for 15 minutes. The aqueous layer wasextracted with EtOAc (2×25 mL). The combined organic extracts werewashed with water (25 mL), brine (25 ml), dried over Na₂SO₄, filteredand evaporated under reduced pressure to afford compound 3a as a brownliquid (5.0 g, crude).

TLC: 80% EtOAc/Hexane (R_(f): 0.30)

¹H NMR (400 MHz, CDCl₃): δ 4.85 (brs, 1H, Exc), 3.80-3.72 (m, 8H),3.13-3.07 (m, 2H), 2.67 (t, J=6.8 Hz, 2H), 1.87-1.76 (m, 2H), 1.43 (s,9H)

LC-MS: m/z=308.3 [M+H]⁺ at RT 2.67 (99.1% purity)

tert-butyl (3-(1, 8-naphthyridin-2-yl) propyl) carbamate (5a)

To a stirred solution of compound 4a (0.500 g, 4.09 mmol, 1.0 equiv.)and compound 3a (1.26 g, crude, 1.0 equiv.) in MeOH (9.17 mL), 50% NaOHsolution (0.314 mL) was added and the reaction mixture was stirred at50° C. for 10 h. After consumption of the starting material (by TLC),volatiles were removed, crude residue was diluted with EtOAc (15 mL) andthe organic layer was washed with water (2×15 mL). The separated organiclayer was dried over Na₂SO₄, filtered and concentrated under reducedpressure to afford brown syrup, which was purified by columnchromatography on neutral alumina (80% EtOAc:Hexane) to provide compound5a (0.980 g, 83.3%) as an off-white solid.

TLC: EtOAc

¹H NMR (500 MHz, CDCl₃): δ 9.09 (s, 1H), 8.17-8.15 (m,1H), 8.10 (d,J=8.0 Hz, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.41 (t, J=15.0, 1H), 4.76 (brs,1H, Exc), 3.25-3.21 (m, 2H), 3.09 (t, J =10.0 Hz, 2H), 2.14-2.08 (m,2H), 1.42 (s, 9H)

LC-MS: m/z=288 [M−H]⁻ at RT 2.86 (94.7%)

tert-butyl (3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl)carbamate (S-024)

To a stirred solution of compound 5a (0.25 g, 0.87 mmol, 1.00 equiv.) inMeOH (5 mL), Rh/C (catalytic, 5 wt %) was added under N₂ atmosphere andstirred at RT for 8 h under hydrogen (balloon pressure) atmosphere.After completion of the starting material, the reaction mixture wasfiltered through pad of celite, washed with MeOH (5 mL). The filtratewas evaporated under reduced pressure to afford compound S-024 (0.18 g,71.1%) as a white solid.

TLC: EtOAc

¹H NMR (400 MHz, CDCl₃): δ 7.05 (d, J=7.6 Hz, 1H), 6.34 (d, J =7.2 Hz,1H), 5.44 (s, 1H), 4.78 (brs, 1H, Exc), 3.41-3.38 (m, 2H), 3.16 (d,J=6.0 Hz, 2H), 2.68 (t, J=6.0 Hz, 2H), 2.59 (t, J=7.6 Hz, 2H),1.93-1.81(m, 4H), 1.44 (s, 9H)

LC-MS: m/z=292.3 [M+H]⁺ at RT 3.41(97.9% purity)

3-(5, 6, 7 ,8-tetrahydro-1, 8-naphthyridin-2-yl) propan-1-amine (6b)

To a stirred solution of S-024 (0.25 g, 0.85 mmol, 1.00 equiv.) in DCM(5 mL), cooled to 0° C., TFA (0.13 mL, 1.69 mmol, 2.00 equiv.) wasadded. The reaction was warmed to RT and stirred for 4 h. Afterconsumption of the starting material (by TLC), the reaction mixture wasconcentrated under reduced pressure to afford crude compound 6b (0.30 g)as a thick syrup which was used in the next step without purification.

5-bromo-2-(difluoromethoxy) pyridine (2)

To a stirred solution of compound 1 (4.50 g, 25.8 mmol, 1.0 equiv.) inanhydrous MeCN (80 mL), sodium 2-chloro-2,2-difluoroacetate (4.89 g,31.0 mmol, 1.20 equiv.) was added at RT and stirred at 70° C. for 48 h.After consumption of the starting material (by TLC), the reactionmixture was brought to RT and diluted with NH₄Cl solution (30 mL). Theaqueous layer was extracted with EtOAc (2×40 mL). The combined organiclayers were washed with brine solution (2×50 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to give thecrude compound which was purified by column chromatography (2%EtOAc/hexane) to afford compound 2 (3.2 g, 57%) as pale yellow syrup.

TLC: 5% EtOAc/Hexane (R_(f:) 0.5) z

¹H NMR (400 MHz, CDCl₃): δ 8.25 (d, J=2.8 Hz, 1H), 7.82 (dd, J=2.4, 6.4Hz, 1H), 7.40 (t, J=72.8 Hz, 1H), 6.83 (d, J=8.8 Hz, 1H)

LC-MS: m/z=224.7 [M+H]⁺ at RT 4.22 (98.2% purity)

(E)-tert-butyl 3-(6-(difluoromethoxy) pyridin-3-yl) acrylate (3)

To a stirred solution of tert-butyl acrylate (9.99 g, 78.1 mmol, 3.50equiv.), Et₃N (8.5 mL, 60.2 mmol, 2.70 equiv.), N-methyl pyrrolidine (20mL), Tritolylphosphine (1.17 g, 3.52 mmol, 0.16 equiv.) followed byPd(OAc)₂ (0.50 g, 2.22 mmol, 0.09 equiv.) were added. The temperaturewas gradually raised to 90° C. and compound 2 (5.00 g, 22.3 mmol, 1.0equiv.) in NMP (10 mL) was added drop wise and stirred at 90° C. for 12h. After consumption of the starting material (by TLC), the reactionmixture was filtered through pad of celite and washed with EtOAc (50mL). The combined filtrate was washed with cold water (2×50 mL) followedby NaOCl (50 mL), brine solution (50 mL). The organic layer was driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressureto give the crude residue which was purified by column chromatography(3% EtOAc/hexane) to afford compound 3 (4.0 g, 66%) as yellow solid.

TLC: 5% EtOAc/Hexane (R_(f): 0.5)

¹H NMR (400 MHz, CDCl₃): δ 8.28 (d, J=2.4 Hz, 1H), 7.88 (dd, J=2.0, 6.4Hz, 1H), 7.56 (d, J=16.0 Hz, 1H), 7.55 (t, J=45.6 Hz, 1H), 6.91 (d,J=8.4 Hz, 1H), 6.34 (d, J=16.0 Hz, 1H), 1.53 (s, 9H)

LC-MS: m/z=272 [M+H]⁺ at RT 4.16 (99.5% purity)

(S)-tert-butyl 3-(benzyl ((R)-1-phenylethyl)amino)-3-(6-methoxypyridin-3-yl) propanoate (5)

To a stirred solution of compound 4 (0.39 g, 1.85 mmol, 2.0 equiv.) inTHF (5 mL), cooled to −30° C., n-BuLi (0.66 mL, 1.65 mmol, 1.79 equiv.)was added and then cooled to −78° C. Compound 3 (0.25 g, 0.92 mmol, 1.0equiv.) dissolved in THF (3 mL) was added to the reaction mixture,stirred for 30 min and quenched with saturated ammonium chloride. Thereaction mixture was extracted with EtOAc (2 x 20 mL). The combinedorganic extracts were washed with 10% AcOH, brine solution which wasdried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to give the crude compound (mixture of 3 and 5, 0.17 g) asthick syrup, which was directly used in the next step.

TLC: 5% EtOAc/Hexane (R_(f): 0.5)

LC-MS: m/z=483 [M+H]⁺ at RT 4.66 (75.1% purity)

Synthesis of (S)-tert-butyl 3-amino-3-(6-(difluoromethoxy) pyridin-3-yl)propanoate (S-029)

To a stirred solution of compound 5 (0.80 g, crude mixture) in EtOAc (5mL) and AcOH (0.5 mL), 20% Pd(OH)₂ (50 mg) was added under N₂atmosphere. The reaction mixture was stirred under H₂ atmosphere (40psi) at RT for 2 h. After consumption of the starting material(monitored by TLC), the reaction mixture was filtered through a pad ofcelite. Filtrate was concentrated under reduced pressure to afford crudecompound which was purified by column chromatography (2% MeOH/DCM) tofurnish S-029 (0.3 g, 63%) as yellow syrup.

TLC: 5% MeOH/DCM (R_(f): 0.3)

¹H NMR (400 MHz, CDCl₃): δ 8.17 (d, J=2.8 Hz, 1H), 7.78 (dd, J=2.4, 6.4Hz, 1H), 7.44 (t, 73.2 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 4.43-4.40 (m,1H), 2.65-2.56 (m, 2H), 1.42 (s, 9H)

LC-MS: m/z=274 [M+H]⁺ at RT 2.76 (99.8% purity)

(S, E)-tert-Butyl 3-(6-(tert-butoxy)pyridin-3-yl)-3-((2,2-dimethoxyethylidene) amino) propanoate (7)

To a stirred solution of dimethoxy acetaldehyde (0.44 mL, 2.50 mmol,1.20 equiv., 60% in water) in DCM (10 mL), cooled to 0° C., anhydrousMgSO₄ (10 g) was added followed by S-029 (600 mg, 2.08 mmol, 1.0 equiv.)in DCM (5 mL). The reaction was continued at RT for 2 h and filteredthrough a pad of celite, the filtrate was concentrated under reducedpressure to afford compound 7 (650 mg, crude) as a yellow liquid whichwas used in the next step without any purification.

TLC: 5% MeOH/DCM (R_(f): 0.5)

(S)-tert-butyl 3-(6-(difluoromethoxy) pyridin-3-yl)-3-((2,2-dimethoxyethyl )amino) propanoate (8):

To a stirred solution of compound 7 (0.65 g, crude, 1.0 equiv.) in MeOH(7 mL), cooled to 0° C., NaBH(CN)₃ (0.13 g, 2.09 mmol, 1.20 equiv.) wasadded and the reaction mixture was stirred at RT for 2 h. Afterconsumption of the starting material (by TLC), MeOH was removed underreduced pressure to give the crude residue which was diluted with water(10 mL) and extracted with EtOAc (2×10 ml). The combined organicextracts were dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure to give the crude material which was purified bycolumn chromatography (2% MeOH/DCM) to afford compound 8 (0.52 g, 79%)as a thick syrup.

TLC: 5% MeOH/DCM (R_(f): 0.7)

¹H NMR (400 MHz, CDCl₃): δ 8.13 (d, J=2.0 Hz, 1H), 7.75 (dd, J=2.4, 6.0Hz, 1H), 7.44 (t, J=73.2 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 4.43-4.37 (m,2H), 4.06-4.02 (m, 1H), 3.60-3.54 (m, 2H), 3.35 (s, 3H) 3.31 (s, 3H),2.66-2.57 (m, 2H), 1.39 (s, 9H)

LC-MS: m/z=377 [M+H]⁺ at RT 2.96 (92.3% purity)

(S)-tert-butyl 3-(6-(difluoromethoxy)pyridin-3-yl)-3-(1-(2,2-dimethoxyethyl)-3-(3-(5, 6, 7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl) ureido) propanoate (10)

To a stirred solution of compound 8 (375 mg, 0.99 mmol, 1.0 equiv.) indry DCM (5 mL), cooled to 0° C., triphosgene (1.50 mL, 2.99 mmol, 3.00equiv., 20% in PhMe) followed by Et₃N (0.30 mL, 2.09 mmol, 2.10 equiv)were added. The reaction mixture was slowly brought to RT and stirredfor 2 h. After completion of the starting material, volatiles wereevaporated to afford the crude compound 9, which was used directly inthe next step without purification. A solution of compound 9 in DCE (2mL) was added to a solution of compound 6b (400 mg, 1.32 mmol, 1.32equiv.) in DCM (5 mL), Et₃N (0.55 mL, 3.98 mmol, 4.00 equiv) at 0° C.and stirred at RT for 4 h. After consumption of the starting material(monitored by TLC), the reaction mixture was concentrated under reducedpressure to give the crude residue which was purified by columnchromatography (2% MeOH/DCM) to afford compound 10 (0.40 g, 67%) as athick syrup.

TLC: 5% MeOH/DCM (R_(f): 0.2)

¹H NMR (400 MHz, CDCl₃): δ 8.13 (d, J=2.8 Hz, 1H), 7.79 (dd, J=2.4, 6.4Hz, 1H), 7.62 (tt, J=72.8 Hz, 1H), 7.12 (d, J=6.4 Hz, 1H), 6.86 (d,J=8.4 Hz, 1H), 6.36 (d, J=3.6 Hz, 1H), 6.22 (t, J=4.8 Hz, 1H), 5.75 (t,J=7.6 Hz, 1H), 4.26 (t, J=5.2 Hz, 1H), 3.45-3.38 (m, 8H), 3.27-3.13 (m,3H), 2.99-2.93 (m, 2H), 2.71-2.59 (m, 5H), 1.93-1.83 (m, 5H), 1.39 (s,9H)

LC-MS: m/z=594 [M+H]^(⇄) at RT 3.42 (88.1% purity)

(S)-tert-Butyl 3-(6-(difluoromethoxy) pyridin-3-yl)-3-(2-oxo-3-(3-(5, 6,7 ,8-tetrahydro-1, 8-naphthyridin-2-yl)propyl)-2,3-dihydro-1H-imidazol-1-yl) propanoate (11)

To a stirred solution of compound 10 (0.20 g, 0.34 mmol, 1.0 equiv.) inTHF (4 mL), at −10° C., 1 M sulphuric acid (0.8 mL) was added. Thereaction was slowly warmed to RT and stirred for 10 h. After consumptionof the starting material (monitored by LCMS), THF was removed and thecrude residue was neutralized with sodium hydroxide (50 wt %) till pH˜7. The aqueous layer was extracted with 5% MeOH/DCM (3×20 mL) and thecombined organic extracts were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to furnish compound 11 (0.22 g,crude) as a syrup.

TLC: 10% MeOH/DCM (R_(f): 0.5)

LC-MS: m/z=530 [M+H]⁺ at RT 4.06 (72.8% purity)

(S)-tert-Butyl 3-(6-(difluoromethoxy) pyridin-3-yl)-3-(2-oxo-3-(3-(5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) propyl) imidazolidin-1-yl)propanoate (12)

To a stirred solution of compound 11 (0.45 g, crude, 1.0 equiv.) in EtOH(8 mL), 20% Pd/C (200 mg) was added under N₂ atmosphere. The reactionmixture was stirred under H₂ atmosphere (40 psi) at RT for 36 h. Afterconsumption of the starting material the reaction mixture was filteredthrough a pad of celite, the filtrate was concentrated under reducedpressure to afford crude compound 12, which was purified by chiralpreparative HPLC to afford compound 12 (450 mg, crude) as an off-whitesolid.

TLC: 10% MeOH/DCM (R_(f): 0.5)

LC-MS: m/z=532.6 [M+H]⁺ at RT 3.99 (80.1% purity)

(S)-3-(6-(difluoromethoxy) pyridin-3-yl)-3-(2-oxo-3-(3-(5, 6, 7,8-tetrahydro-1, 8-naphthyridin-2-yl) propyl) imidazolidin-1-yl)propanoic acid (Compound A1 in Table 1)

To a stirred solution of compound 12 (0.40 g, crude, 1.0 equiv.) in DCM(2 mL), cooled to −10° C., TFA (0.5 mL) was added under N₂ atmosphere.The reaction was slowly brought to RT and stirred for 2 h; afterconsumption of the starting material, volatiles were evaporated toafford crude (400 mg) compound, which was purified by chiral preparativeHPLC to afford compound A1 as an off-white solid.

TLC: 10% MeOH/DCM (R_(f): 0.3)

¹H NMR (400 MHz, CD₃OD): δ 8.20 (d, J=2.4 Hz, 1H), 7.85 (dd, J=2.4, 6.4Hz, 1H), 7.53 (t, J=2.4 Hz, 1H), 7.50 (d, J=7.2 Hz, 1H), 6.98 (d, J=8.4Hz, 1H), 6.57 (d, J=7.2 Hz, 1H), 5.51 (dd, J=3.6, 8.0 Hz, 1H), 3.68-3.61(m, 1H), 3.52-3.46 (m, 3H), 3.38 (m, 1H), 3.24-3.17 (m, 1H), 3.07-2.98(m, 2H), 2.90-2.62 (m, 6H), 2.09-1.81 (m, 4H).

LC-MS: m/z=476 [M+H]⁺ at RT 2.78 (97.9% purity)

HPLC purity: 96.4%; Chiral Purity: 99%

Example 2 Synthesis of(S)-3-(6-(difluoromethoxy)pyridin-3-yl)-3-(2-oxo-3-((3-((5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)methyl)oxetan-3-yl)methyl)imidazolidin-1-yl)propanoicacid (Compound A2 in Table 1)

The synthetic route is the same as Example 1 except for substituting atStep-8:(3-((5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)methyl)oxetan-3-yl)methanamine

for compound 6b and continuing the synthetic scheme using the samereaction conditions.

Example 3 Synthesis of(S)-3-(3-(2,2-difluoro-3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl)-2-oxoimidazolidin-1-yl)-3-(6-(difluoromethoxy)pyridin-3-yl)propanoicacid (Compound A3 in Table 1)

The synthetic route is the same as Example 1 except for substituting atStep-8:2,2-difluoro-3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propan-1-amine

for compound 6b and continuing the synthetic scheme using the samereaction conditions.

Example 4 Synthesis of(S)-3-(3-(2,2-difluoro-3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl)-2-oxoimidazolidin-1-yl)-3-(6-methoxypyridin-3-yl)propanoicacid (Compound A4 in Table 1)

The synthetic scheme is the same as Example 3, except the synthesis inStep 1 uses sodium 2-chloroacetate instead of sodium2-chloro-2,2-difluoroacetate. The synthesis proceeds under the sameconditions as Example 3.

The synthesis of the Gem-Difluoride fragment H, shown in the dashedboxes, is shown in Schemes 2-4:

The preparation of intermediates C and E is detailed in the literatureand is depicted above (for C; Campbell, J. E.; Hewitt, M. C.; Jones, P.;Xie, L. WO2011150156 and for E; Seebach, D.; Maestro, M. A.; Sefkow, M.;Adam, G.; Hintermann, S.; Neidlein, A. Liebigs Ann. Chem., 1994,701-717). The formation of the dianion of E has been described, and itwas used to displace substituted benzylic chlorides (Bradshaw, B.;Evans, P.; Fletcher, J.; Lee, A. T. L.; Mwashimba, P. G.; Oehlrich, D.;Thomas, E. J.; Davies, R. H.; Allen, B. C. P.; Broadley, K. J.;Hamrouni, A.; Ascargueil, C. Org. Biomol. Chem., 2008, 6, 2138-2157.);this event similarly affords complex dithiane F. Fluorodesulfurizationof thioketals has been described with several reagents (Sondej, S. C.;Katzenellenbogen, J. A. J. Org. Chem., 1986, 51, 3508-13.); intermediateG is reduced and deprotected as described in the literature (Wang, J.US20040038963). Fragment H is inserted into the known route to producethe target compounds.

Known β-ketoester P is cyclized, then ketalized with 1,2-dithiol to formlactam Q. Ring opening with a phosphonate enolate affords Horner-Emmonsreagent R, which is immediately followed by a Friedlander reaction tointersect scheme 2, route 1 at intermediate F (Yasuda, N.; Hsiao, Y.;Jensen, M. S.; Rivera, N. R.; Yang, C.; Wells, K. N.; Yau, J.; Palucki,M.; Tan, L.; Dormer, P. G.; Volante, R. P.; Hughes, D. L.; Reider, P. J.J. Org. Chem., 2004, 69, 1959-1966).

Reformatsky reaction of known 1,8-naphthyridine S affords carbinol T(Linderman, R. J.; Graves, D. M. J. Org. Chem., 1989, 54, 668). Bartondeoxygenation utilizing conditions reported for very similar substratesaffords U (Hallinanm, E. A.; Hagan, T. J.; Husa, R. K.; Ysymbalov, S.;Rao, S. N.; vanHoeck, J.-P.; Rafferty, M. F.; Stapelfeld, A.; Savage, M.A.; Reichman, M. J. Med. Chem. 1993, 36, 3298-3299). Reduction of theester followed by triflation and displacement affords azide V. Selectivereduction affords the requisite amine H (Wang, J. US20040038963).

The synthesis of the Oxetane fragment N, shown in the dashed boxes, isshown in Schemes 5-7:

Commercially available ester J is transformed to the Weinreb amide K,then treated with methyl Grignard to form ketone L (Nahm, S.; Weinreb,S. M. Tetrahedron Lett. 1981, 22, 3815.). A Friedlander condensationwith 2-aminonicotinaldehyde affords 1,8-napthyridine M (Friedlander, P.Ber. Dtsch. Chem. Ges. 1882, 15, 2572). A well-precedented reductionaffords the requisite tetrahydro-fragment N (Wang, J. US20040038963).

Commercially available lactam P is protected as a Boc-carbonate andopened with a Grignard reagent to form ketone R. A similarFriedlander/reduction/deprotection sequence affords fragment N.

Aminoalcohol T is protected as a carbonate and oxidized. Theintermediary aldehyde U is treated with a methyl Grignard reagent andoxidized to the ketone R. A similar Friedlander/reduction/deprotectionsequence affords requisite fragment N.

Equivalents

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments and methods described herein. Such equivalents are intendedto be encompassed by the scope of the present invention.

All patents, patent applications, and literature references cited hereinare hereby expressly incorporated by reference.

What is claimed:
 1. A method of treating a condition selected from thegroup consisting of bone resorption, osteoporosis, restenosis, diabeticretinopathy, macular degeneration, angiogenesis, atherosclerosis,cancer, tumor growth, and metastasis; eliciting an αvβ3 integrinreceptor antagonizing effect wherein the effect is inhibition of boneresorption, restenosis, angiogenesis, diabetic retinopathy, maculardegeneration, tumor growth, or metastasis; or inhibiting bone resorptionin a human subject in need thereof, comprising administering to thesubject a therapeutically effective amount of a compound of formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein X isselected from CH and N; Y is selected from CH and N; R₁ is C₁-C₆ alkoxywherein said C₁-C₆ alkoxy is substituted with 0, 1, 2, 3, 4, or 5fluorine atoms; and R₂ and R₃ are each independently selected from H andF, or R₂ and R₃ taken together with the carbon atom to which they areattached form a 3- or 4-membered carbocyclic or heterocyclic ring,provided that the compound of formula I contains at least one fluorineatom.
 2. The method of claim 1, comprising administering to the subjecta therapeutically effective amount of a compound of formula II:

or a pharmaceutically acceptable salt or solvate thereof, wherein X isselected from CH and N; Y is selected from CH and N; R₁ is C₁-C₆ alkoxywherein said C₁-C₆ alkoxy is substituted with 0, 1, 2, 3, 4, or 5fluorine atoms; and R₂ and R₃ are each independently selected from H andF, or R₂ and R₃ taken together with the carbon atom to which they areattached form a 3- or 4-membered carbocyclic or heterocyclic ring,provided that the compound of formula II contains at least one fluorineatom.
 3. The method of claim 2, comprising administering to the subjecta therapeutically effective amount of a compound of formula III:

or a pharmaceutically acceptable salt or solvate thereof, wherein R₁ isC₁-C₆ alkoxy wherein said C₁-C₆ alkoxy is substituted with 0, 1, 2, 3,4, or 5 fluorine atoms; and R₂ and R₃ are each independently selectedfrom H and F, or R₂ and R₃ taken together with the carbon atom to whichthey are attached form a 3- or 4-membered carbocyclic or heterocyclicring, provided that the compound of formula III contains at least onefluorine atom.
 4. The method of claim 2, comprising administering to thesubject a therapeutically effective amount of a compound of formula IV:

or a pharmaceutically acceptable salt or solvate thereof, wherein R₁ isC₁-C₆ alkoxy wherein said C_(i)-C₆ alkoxy is substituted with 0, 1, 2,3, 4, or 5 fluorine atoms; and R₂ and R₃ are each independently selectedfrom H and F, or R₂ and R₃ taken together with the carbon atom to whichthey are attached form a 3- or 4-membered carbocyclic or heterocyclicring, provided that the compound of formula IV contains at least onefluorine atom.
 5. The method of claim 2, comprising administering to thesubject a therapeutically effective amount of a compound of formula V:

or a pharmaceutically acceptable salt or solvate thereof, wherein R₁ isC₁-C₆ alkoxy wherein said C₁-C₆ alkoxy is substituted with 0, 1, 2, 3,4, or 5 fluorine atoms; and R₂ and R₃ are each independently selectedfrom H and F, or R₂ and R₃ taken together with the carbon atom to whichthey are attached form a 3- or 4-membered carbocyclic or heterocyclicring, provided that the compound of formula V contains at least onefluorine atom.
 6. The method of claim 1, wherein the compound isadministered orally, intravenously, intraperitoneally, topically,subcutaneously, intramuscularly, or transdermally.
 7. The method ofclaim 6, wherein the compound is administered topically.
 8. The methodof claim 1, further comprising administering a second therapy.
 9. Themethod of claim 8, wherein the second therapy comprises an activeingredient selected from the group consisting of: a) an organicbisphosphonate or a pharmaceutically acceptable salt or ester thereof,b) an estrogen receptor modulator, c) a cytotoxic/antiproliferativeagent, d) a matrix metalloproteinase inhibitor, e) an inhibitor ofepidermal-derived, fibroblast-derived, or platelet-derived growthfactors, f) an inhibitor of VEGF, g) an inhibitor of Flk-1/KDR, Flt-1,Tck/Tie-2, or Tic-1, h) a cathepsin K inhibitor, and i) a prenylationinhibitor; and mixtures thereof.
 10. The method of claim 9, wherein thesecond therapy comprises administering an inhibitor of VEGF.
 11. Themethod of claim 1, comprising administering to the subject atherapeutically effective amount of a compound selected from the groupconsisting of:

or a pharmaceutically acceptable salt or solvate thereof.
 12. The methodof claim 1, comprising administering to the subject a therapeuticallyeffective amount of a compound selected from the group consisting of:

or a pharmaceutically acceptable salt or solvate thereof.
 13. The methodof claim 1, wherein the condition is selected from the group consistingof cancer and osteoporosis.
 14. The method of claim 1, wherein thecondition is osteoporosis.
 15. The method of claim 1, wherein the methodis treating a condition selected from the group consisting of boneresorption, osteoporosis, restenosis, diabetic retinopathy, maculardegeneration, angiogenesis, atherosclerosis, cancer, tumor growth, andmetastasis.
 16. The method of claim 15, wherein the condition isdiabetic retinopathy or macular degeneration.
 17. The method of claim15, wherein the condition is cancer.
 18. The method of claim 1, whereinthe method is eliciting an αvβ3 integrin receptor antagonizing effectwherein the effect is inhibition of bone resorption, restenosis,angiogenesis, diabetic retinopathy, macular degeneration, tumor growth,or metastasis.
 19. The method of claim 18, wherein the effect isinhibition of diabetic retinopathy or macular degeneration.
 20. Themethod of claim 1, wherein the method is inhibiting bone resorption.